Mechanism study of copper-mediated one-pot reductive amination of aryl halides using trimethylsilyl azide

Article abstract of DOI:10.1021/jo401474k

Reaction mechanisms of the copper-mediated amination of aryl halides with trimethylsilyl azide (TMSN₃) were analyzed on the basis of the time-course study using reaction monitoring FT-IR, trapping an intermediary aryl azide by the Huisgen reaction, and the analysis of the generated N₂ gas during the reaction. This amination would proceed through multiple pathways via aryl radicals and copper(I) azide.

Full text of DOI:10.1021/jo401474k

Featured Article
pubs.acs.org/joc
Mechanism Study of Copper-Mediated One-Pot Reductive Amination
of Aryl Halides Using Trimethylsilyl Azide
Toshihide Maejima,† Moriatsu Ueda,‡ Jun Nakano,‡ Yoshinari Sawama,† Yasunari Monguchi,*,†
and Hironao Sajiki*,†
†Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
‡Bruker Optics K. K., 1-4-1 Shinkawa, Chuo-ku, Tokyo 104-0033, Japan
S
* Supporting Information
ABSTRACT: Reaction mechanisms of the copper-mediated amination of aryl halides with trimethylsilyl azide (TMSN3) were
analyzed on the basis of the time-course study using reaction monitoring FT-IR, trapping an intermediary aryl azide by the
Huisgen reaction, and the analysis of the generated N2 gas during the reaction. This amination would proceed through multiple
pathways via aryl radicals and copper(I) azide.
aryl azide and subsequent removal of N2 to generate a nitrene
intermediate (Scheme 2). Although the formation of the aryl
INTRODUCTION
■
Primary aromatic amines are widely used as intermediates of
pharmaceuticals, agrochemicals, dyes, and polymers in the
chemical industry.1 Effective synthetic methods for primary
aromatic amines based on the palladium- or copper-catalyzed
cross-coupling reactions between aryl halides and ammonia or
ammonium salts have been developed in less than a decade.2,3
Recently, we have found that the use of trimethylsilyl azide
(TMSN3) instead of an ammonia equivalent for the cross-
coupling also afforded the corresponding primary amine as the
sole product (Scheme 1),4,5 although Ma and Liang
independently reported the aryl azide synthesis under similar
copper-catalyzed conditions using NaN3.6
Scheme 2. Alami’s Copper-Catalyzed Amination of Aryl
Halides
Scheme 1. Copper-Mediated Reductive Amination of a
Variety of Aryl Halides with TMSN3
azide intermediate was confirmed by its Huisgen type reaction
with 4-ethynylanisole, no evidence for the nitrene generation
was indicated.9c Ramana et al. proposed that the aromatic
nucleophilic substitution of electron-deficient aryl halides with
NaN3 would take place using CuSO4, L-proline, and sodium
ascorbate, giving the corresponding aryl azide (Scheme 3),
which could be reduced to the amine in situ, based on the fact
that 2-fluoro-4-iodonitrobenzene underwent the amination at
the more electron-withdrawing but thermodynamically stable
fluorine group rather than at the iodine group.9d Both of these
aminations are considered to proceed via the formation of the
Molander et al. found that primary amines were fairly
frequently and substrate-dependently obtained instead of azides
during the copper-catalyzed aromatic azidation reaction using
aryl halides and NaN3.7 Several syntheses of primary aromatic
amines using NaN3 have been reported8−10 almost at the same
time as our communication4 after Molander’s pioneering but
unintended consequences;7 only two reports provided possible
reaction mechanisms. Alami et al. speculated that a Cu powder-
promoted amination of 3-bromoquinolines or 3-bromocou-
marines proceeded through the formation of the corresponding
Received: July 8, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401474k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Real-time infrared (IR) analysis of the copper-mediated
aromatic amination using a reaction-monitoring FT-IR
spectrometer was carried out to obtain insight into the reaction
process. When TMSN3 was treated with Cu (1.0 equiv) and 2-
aminoethanol (1.25 equiv) in heated DMA (95 °C) in the
absence of the aromatic halide as a substrate, a peak at 2013
cm−1 derived from TMSN3 was time-dependently shifted to
2057 cm−1 over a 1 h period. The newly generated single broad
peak was attributed to the formation of copper(I) azide
(CuN3), which was consistent with the adsorption indicated in
the literature (Figure 2).12,13 A similar time-course of the IR
Scheme 3. Ramana’s Copper-Catalyzed Amination of Aryl
Halides
aryl azide as an intermediate, but a real reducing reagent and
hydrogen source were not identified.
In our previous paper5 on the aromatic amination of aryl
halides using TMSN3, Cu powder, and 2-aminoethanol in N,N-
dimethylacetamide (DMA), we concluded that (1) 2-amino-
ethanol would work as a major hydrogen source because the
amination quantitatively proceeded even without a solvent, (2)
DMA could be a minor hydrogen donor due to the 23%
generation of ethyl 4-aminobenzoate from the corresponding
aryl bromide and TMSN3 even without 2-aminoethanol, and
(3) the reaction would be involved in a single-electron transfer
process because of the strong suppression of the reaction by the
addition of a single-electron scavenger (TCNQ or TCNE). An
advanced reaction mechanistic study of the copper−mediated
reductive amination of aryl halides and TMSN3 in the presence
of 2-aminoethanol using FT-IR and reaction monitoring FT-IR
will now be reported.
RESULTS AND DISCUSSION
■
The azido peak at 2129 cm−1 of TMSN3 in DMA [Figure 1,
spectrum (a)] was shifted to 2012 cm−1 by the addition of 2-
Figure 2. Time-course study using reaction monitoring FT-IR of the
reaction of Cu powder, TMSN3, and 2-aminoethanol in DMA at 95 °C
for 1 h.
Figure 1. IR spectra in DMA of (a) TMSN3; (b) TMSN3 and 2-
aminoethanol; (c) TMSN3 and TBAF.
spectrum was observed for 0.5 h in the presence of ethyl 4-
bromobenzoate (1); during the copper-mediated amination of
1 with TMSN3 and 2-aminoethanol in DMA at 95 °C, the peak
intensity at 2012 cm−1 gradually decreased, and the peak
intensity at 2058 cm−1 increased. The peak at 2058 cm−1 then
slowly decreased from 0.5 to 1 h, and no change was observed
in the spectrum after 1 h (Figure 3). This result would
correspond to the fact that the amination was almost completed
aminoethanol [spectrum (b)]. This peak shift would be
−
attributed to the partial liberation of the N3 ion together
with the formation of TMSO(CH2)2N+H3 because of the
observed similar peak at 2010 cm−1 by the addition of n-
tetrabutylammonium fluoride (TBAF) to the TMSN3 solution
in DMA, partially generating N3 with TBA+ and TMSF
−
[spectrum (c)].11
B
dx.doi.org/10.1021/jo401474k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Scheme 5. Confirmation of Generated Ethyl 4-
Azidobenzoate during the Amination of Ethyl 4-
Bromobenzoate and TMSN3 Using the Huisgen Cyclization
Although ethyl 4-aminobenzoate (2), the copper-mediated
amination product, was obtained as the major product (73%),
formation of the 1,2,3-triazole derivative (5) could also be
detected, but in a low yield (12%) (Scheme 5). Two possible
reaction pathways toward 5 would be considered through (1)
the Huisgen cycloaddition14 of ethynylbenzene (4) with ethyl
4-azidobenzoate, or (2) Ullmann type reaction between 1 and
4-phenyl-1H-1,2,3-triazole (6), which could be first generated
by the Huisgen cycloaddition between 1 and TMSN3. Since the
Ullmann-type reaction scarcely proceeded under the reaction
conditions (3%, Scheme 6), 5 should be obtained via the
formation of ethyl 4-azidobenzoate. Therefore, the formation of
aryl azide would be involved in the present copper-mediated
amination processes.15
Scheme 6. Ullmann-Type Amination of Ethyl 4-
Bromobenzoate (1) and 4-Phenyl-1H-1,2,3-triazole (6)
Figure 3. Time-course study using reaction monitoring FT-IR of the
amination of ethyl 4-bromobenzoate with TMSN3 in the presence of
Cu powder and 2-aminoethanol in DMA at 95 °C for 1 h.
within 1 h. Furthermore, the peak5 at 2126 cm−1 for the aryl
azide (ethyl 4-azidobenzoate) was never detected in the IR
study (Figure 3) during the reaction. These results suggest that
the amination of ethyl 4-bromobenzoate (1) with TMSN3
would mainly proceed without the formation of the ethyl 4-
azidobenzoate intermediate (3), although the azide itself could
be gradually reduced to the corresponding aniline (2) under
the present amination conditions over a 5 h period (Scheme 4).
During the course of the present amination using TMSN3,
the release of N2 gas is indispensable. The N2 gas generated in
the test tube during the amination was analyzed by gas
chromatography (Table 1). N2 (15%) from a test tube filled
with only Ar was detected as a background because the internal
gas in the test tube was collected by the water substitution
method, and the dissolved N2 in H2O was easily contaminated
(entry 1). When the gas in the test tube containing ethyl 4-
bromobenzoate, TMSN3, Cu powder, 2-aminoethanol, and
DMA was measured just after the air was replaced with Ar, 18%
N2 was detected, indicating that nearly no N2 generation took
place (entry 2). The ratio of N2 gas was increased to 60%
during the early stage of the reaction (0.25 h) (entry 3).
Moreover, even without ethyl 4-bromobenzoate (1), 38% N2
was detected after 0.25 h. Therefore, a part of the present
amination would proceed through the removal of N2 from
copper azide before its coupling reaction with the aryl halide
(entries 2 vs 4). The aryl amine (2) would be mainly generated
before the formation of aryl azide (3, Scheme 4), since 3 was
Scheme 4. Reduction of Ethyl 4-Azidobenzoate (3)
A further investigation to acquire the aryl azide as a possible
intermediate, which could not be detected by the reaction
monitoring FT-IR (Figure 3), through use of the Huisgen
cycloaddition by the addition of ethynylbenzene (4) to the
reaction mixture of ethyl 4-bromobenzoate (1) and TMSN3
using copper and 2-aminoethanol was carried out (Scheme 5).
C
dx.doi.org/10.1021/jo401474k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
azide (D) by the reductive elimination of the Cu(0) species,19
which would be gradually reduced to the primary aromatic
amine (E) (Scheme 4).
Table 1. Analysis of Nitrogen Gas Generated during the
Amination Using Ethyl 4-Bromobenzoate (1) and TMSN3
CONCLUSION
■
In conclusion, we proposed reaction mechanisms for the
copper-mediated amination of aryl halides with TMSN3 by IR
study and Huisgen reaction combined with the analysis of the
generated N2 gas during the reaction. Aromatic amines would
be generated through multiple pathways via aryl radicals and
copper(I) azide. Although the formation of aryl azide as an
intermediate was confirmed, the amination would rather
proceed through an aryl copper(II)−amine complex (C,
Scheme 7) based on the significant N2 release during the
early stage of the reaction.
entry
time (h)
N2 (%)
Ar (%)
a
1
2
3
background
15
80
74
32
55
0
18
60
38
0.25
0.25
b
4
a
The measured N2 should be contaminated by the dissolved N2 in
H2O during the water-substituted method for the internal gas
collection in a test tube. Without ethyl 4-bromobenzoate.
b
EXPERIMENTAL SECTION
not detected during the reaction by the IR study despite its
non-short-lived nature (Scheme 4).
■
General Experimental. All reagents were obtained from
commercial sources and used without further purification. Chemical
shifts of NMR spectra are expressed in parts per million (ppm) based
on an internal standard (1H NMR: δ = 7.26 ppm and 13C NMR: δ =
77.0 ppm for CDCl3). The ESI mass spectra were taken by a TOF
instrument. Gas composition was analyzed by gas chromatography
equipped with a thermal conductivity detector and a carbon molecular
sieve (60/80 mesh)-packed column (4.5 m, 3.2 mm, i.d., SUS).
IR Spectra in DMA (Figure 1). IR spectra of reagents in DMA
were directly measured. The samples were prepared as follows: (a)
TMSN3 (66.4 μL, 500 μmol) was dissolved in DMA (500 μL); (b)
TMSN3 (66.4 μL, 500 μmol) and 2-aminoethanol (37.4 μL, 625
μmol) were dissolved in DMA (500 μL); (c) TMSN3 (66.4 μL, 500
μmol) and TBAF·3H2O (197 mg, 625 μmol) were dissolved in DMA
(500 μL).
A possible reaction mechanism of the present amination is
depicted in Scheme 7. We assumed that an aryl anion radical
would form by a single-electron transfer from Cu powder to an
aromatic ring of the haloarene and undergo the elimination of a
halide ion (X−) to generate the corresponding aryl radical.16 At
the same time, copper(I) azide would be produced together
with the trimethylsilyl (TMS)-protected 2-aminoethanol from
TMSN3 and 2-aminoethanol. Copper(I) azide would then be
subjected to either a removal of N2 gas to form copper(I)
complex (A)17,18 or an oxidative insertion of the aryl radical to
afford the aryl copper(II) azide complex (B). The aryl
copper(II) complex (C)17,18 would be generated by the
oxidative coupling of the aryl radical with the copper(I)
complex (A) or by the removal of N2 from the aryl copper(II)
azide complex (B), and subsequent elimination of copper
species would afford the desired primary aromatic amine (E).
The intermediate (B) would convert to the corresponding aryl
Time-Course Study Using Reaction Monitoring FT-IR for the
Reaction of Copper Powder, TMSN3, and 2-Aminoethanol in
DMA at 95 °C for 1 h (Figure 2). A mixture of copper powder (127
mg, 2.00 mmol), 2-aminoethanol (150 μL, 2.50 mmol), and TMSN3
(265 μL, 2.00 mmol) in DMA (2 mL) in a 10 mL two-neck flask was
Scheme 7. Proposed Reaction Mechanism
D
dx.doi.org/10.1021/jo401474k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
stirred under an Ar atmosphere (balloon) at 95 °C, and the IR peak of
the mixture was monitored vs time.
2-aminoethanol (52.0 μL, 868 μmol) in DMA (700 μL) in a 15 mL
test tube was stirred under an Ar atmosphere (balloon) at 95 °C using
an organic synthesizer. After the complete consumption of ethyl 4-
bromobenzoate was confirmed by TLC analyses (n-hexane/EtOAc,
2:1), the mixture was diluted with EtOAc (10 mL) and then filtered
through a Celite pad. The pad was successively washed with EtOAc
(20 mL), H2O (25 mL), and a concd aq ammonia solution (5 mL).
After the two layers were separated, the aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica-gel column
chromatography with n-hexane/EtOAc (5:1 → 2:1 → 1:1) as the
eluent to afford ethyl 4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoate (5)
as a white solid in 3% yield (3.4 mg, 11.5 μmol). The spectra data are
shown for the experiment for Scheme 5.
Analysis of Nitrogen Gas Generation during the Amination
Using Ethyl 4-Bromobenzoate and TMSN3 (Table 1). A mixture
of ethyl 4-bromobenzoate (1) (80.1 μL, 500 μmol), copper powder
(63.5 mg, 1.00 mmol), 2-aminoethanol (74.9 μL, 1.25 mmol), and
TMSN3 (133 μL, 1.00 mmol) in DMA (1 mL) in a 15 mL test tube
was stirred under an Ar atmosphere at 95 °C using an organic
synthesizer. After the reaction, the gas in the test tube was collected
over water and analyzed by gas chromatography. Helium was used as
the carrier gas at the flow rate of 40 mL/min. The injector and
detector temperatures were both 150 °C. The column temperature
was 40 °C.
Time-Course Study Using Reaction Monitoring FT-IR for the
Amination of Ethyl 4-Bromobenzoate with TMSN3 in the
Presence of Copper Powder and 2-Aminoethanol in DMA at
95 °C for 1 h (Figure 3). A mixture of ethyl 4-bromobenzoate (1)
(160 μL, 1.00 mmol), copper powder (127 mg, 2.00 mmol), 2-
aminoethanol (150 μL, 2.50 mmol), and TMSN3 (265 μL, 2.00 mmol)
in DMA (2 mL) in a 10 mL two-neck flask was stirred under an Ar
atmosphere (balloon) at 95 °C, and the IR peak of the mixture was
monitored vs time.
Reduction of Ethyl 4-Azidobenzoate (Scheme 4). A mixture of
ethyl 4-azidobenzoate (3) (65.9 mg, 500 μmol), copper powder (63.5
mg, 1.00 mmol), and 2-aminoethanol (74.9 μL, 1.25 mmol) in DMA
(1 mL) in a 15 mL test tube was stirred under an Ar atmosphere
(balloon) at 95 °C using an organic synthesizer. After the complete
consumption of ethyl 4-bromobenzoate was confirmed by TLC
analyses (n-hexane/EtOAc, 2:1), the mixture was diluted with EtOAc
(10 mL) and then filtered through a Celite pad. The pad was
successively washed with EtOAc (20 mL), H2O (25 mL), and concd
aq ammonia solution (5 mL). After the two layers were separated, the
aqueous layer was extracted with EtOAc (2 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
dissolved in CDCl3, and the ratio of 3 and ethyl 4-aminobenzoate (2)
1
1
was determined by the H NMR analysis. The H NMR spectral data
For entry 1: Without the addition of any reagents, air inside the test
tube (15 mL) was replaced with Ar, and then the gas inside the test
tube was immediately collected over water.
For entry 2: Ethyl 4-bromobenzoate (1), copper powder, 2-
aminoethanol, TMSN3, and DMA were placed in the test tube, and
the air inside the test tube was replaced with Ar. The gas inside the test
tube was then collected over water.
For entry 3: The reaction mixture was stirred at 95 °C for 0.25 h,
and then the gas inside the test tube was collected over water.
For entry 4: The reaction mixture was carried out in the absence of
ethyl 4-bromobenzoate (1). After the mixture was stirred for 0.25 h,
the gas inside the test tube was collected over water.
is shown below for the experiment for Scheme 5.
Confirmation of Generated Ethyl 4-Azidobenzoate during
the Amination of Ethyl 4-Bromobenzoate and TMSN3 Using
Huisgen Cyclization (Scheme 5). A mixture of ethyl 4-
bromobenzoate (1) (80.1 μL, 500 μmol), ethynylbenzene (4) (54.9
μL, 500 μmol), copper powder (63.5 mg, 1.00 mmol), 2-aminoethanol
(74.9 μL, 1.25 mmol), and TMSN3 (133 μL, 1.00 mmol) in DMA (1
mL) in a 15 mL test tube was stirred under an Ar atmosphere
(balloon) at 95 °C using an organic synthesizer. After the complete
consumption of ethyl 4-bromobenzoate was confirmed by TLC
analyses (n-hexane/EtOAc, 2:1), the mixture was diluted with EtOAc
(10 mL) and then filtered through a Celite pad. The pad was
successively washed with EtOAc (20 mL), H2O (25 mL), and a concd
aq ammonia solution (5 mL). After the two layers were separated, the
aqueous layer was extracted with EtOAc (2 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica-gel column chromatography with n-hexane/EtOAc
(5:1 → 2:1) as the eluent.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra of compounds (2 and 5), IR spectra
of tetrabutylammonium azide and compound (3), IR spectra of
the time-course study using reaction monitoring FT-IR for the
reaction of 3 in the presence of copper powder and 2-
aminoethanol, and IR spectra of the time-course study using
reaction monitoring FT-IR for the reaction of ethyl 4-
bromobenzoate (1) with copper powder, and 2-aminoethanol
in DMA in the presence of ethynylbenzene (4). This material is
available free of charge via the Internet at http://pubs.acs.org.
Ethyl 4-aminobenzoate (2):3a 73% (60.0 mg, 363 μmol) as a pale
yellow solid; mp 92−94 °C; IR (ATR) νmax 3416, 3340, 3218, 2983,
2899, 1678, 1631, 1592, 1511, 1473, 1440, 1366, 1309, 1272, 1169,
1
1122, 1023, 844, 770, 699, 638, 501 cm−1; H NMR (400 MHz) δ
7.85 (d, J = 7.9 Hz, 2H), 6.62 (d, J = 7.9 Hz, 2H), 4.31 (q, J = 7.1 Hz,
2H), 4.13 (br s, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz) δ
166.8, 150.9, 131.5, 119.9, 113.8, 60.3, 14.4; MS (EI) m/z 165 (M+,
44), 137 (15), 120 (100), 92 (21), 65 (17); HRMS (ESI) calcd for
C9H11NO2 (M+) 165.07898, found 165.07823.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sajiki@gifu-pu.ac.jp. Phone/Fax: (+81)-58-230-8109.
■
Ethyl 4-(4-phenyl-1H-1,2,3-triazol-yl)benzoate (5):20 12% (17.9
mg, 61.0 μmol) as a white solid; mp 178−180 °C; IR (ATR) νmax
3120, 3098, 2984, 2933, 1707, 1605, 1519, 1456, 1435, 1408, 1364,
1313, 1273, 1226, 1177, 1103, 1037, 1020, 992, 851, 820, 773, 763,
Notes
1
694 cm−1; H NMR (500 MHz) δ 8.27 (s, 1H), 8.22 (d, J = 8.8 Hz,
The authors declare no competing financial interest.
2H), 7.89−7.92 (m, 4H), 7.46 (dd, J = 7.8, 7.2 Hz, 2H), 7.38 (t, J = 7.8
Hz, 1H), 4.42 (q, J = 7.3 Hz, 2H), 1.43 (t, J = 7.3 Hz, 3H); 13C NMR
(125 MHz) δ 165.4, 148.7, 139.9, 131.3, 130.5, 129.8, 128.9, 128.6,
125.8, 119.7 117.3, 61.4, 14.3; MS (ESI) m/z 293 (M+, 2), 265 (100),
237 (89), 220 (22), 207 (23), 192 (65), 165 (37), 116 (52), 89 (46),
76 (26), 65 (11); HRMS (ESI) calcd for C17H15N3O2 [(M + Na)+]
316.10620, found 316.10547.
Ullmann-Type Amination of Ethyl 4-Bromobenzoate and 4-
Phenyl-1H-1,2,3-triazole (6) (Scheme 6). A mixture of ethyl 4-
bromobenzoate (1) (55.6 μL, 347 μmol), 4-phenyl-1H-1,2,3-triazole
(6)21 (50.4 mg, 347 μmol), copper powder (44.1 mg, 694 μmol), and
ACKNOWLEDGMENTS
We sincerely thank Toyobo Co. Ltd., for the kind gift of
TMSN3.
■
REFERENCES
■
(1) (a) Vogt, P. F.; Gerulis, J. J. Amines, Aromatic. in Ullmann’s
Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2005.
(b) Hunger, K. Industry Dyes: Chemistry, Properties and Applications;
Wiley-VCH: Weinheim, 2003. (c) Lawrence, S. A. Amines: Synthesis,
E
dx.doi.org/10.1021/jo401474k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Properties and Application; Cambrige University Press: Cambrige,
2004.
Angew. Chem., Int. Ed. 2001, 40, 2004−2021. (d) Kolb, H. C.;
Sharpless, K. B. Drug Discovery Today 2003, 8, 1128−1137.
(15) The copper-mediated amination of ethyl 4-bromobenzoate (1)
with TMSN3 and 2-aminoethanol in DMA in the presence of
ethynylbenzene (4) was monitored by the reaction-monitoring FT-IR
spectrometer, but the formation of ethyl 4-azidobenzoate (3) was not
confirmed (2126 cm−1, see the Supporting Information). The IR study
indicated that the reaction proceeded in a somewhat different manner
from the case without 4 probably because of the involvement of
copper with acetylene, e.g., a possible formation of copper acetylide.
The data are shown in the Supporting Information.
(2) For an example using palladium catalyst, see: (a) Shen, Q.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028−10029. (b) Surry, D.
S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354−10355.
(c) Schulz, T.; Torborg, C.; Enthaler, S.; Schaffner, B.; Dumrath, A.;
̈
Spannenberg, A.; Neumann, H.; Borner, A.; Beller, M. Chem.Eur. J.
̈
2009, 15, 4528−4533. (d) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 11049−11061.
(3) For an example using copper catalyst, see: (a) Kim, J.; Chang, S.
Chem. Commun. 2008, 3052−3054. (b) Xia, N.; Taillefer, M. Angew.
Chem. 2009, 121, 343−345; Angew. Chem., Int. Ed. 2009, 48, 337−339.
(c) Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009,
74, 4542−4546. (d) Xu, H.; Wolf, C. Chem. Commun. 2009, 3035−
3037. (e) Wang, D.; Cai, Q.; Ding, K. Adv. Synth. Catal. 2009, 351,
1722−1726. (f) Elmkaddem, M. K.; Fischmeister, C.; Thomas, C. M.;
Renaud, J.-L. Chem. Commun. 2010, 46, 925−927. (g) Wu, Z.; Jiang,
Z.; Wu, D.; Xiang, H.; Zhou, X. Eur. J. Org. Chem. 2010, 1854−1857.
(h) Meng, F.; Zhu, X.; Li, Y.; Xie, J.; Wang, B.; Yao, J.; Wan, Y. Eur. J.
Org. Chem. 2010, 6149−6152. (i) Thakur, K. G.; Ganapathy, D.;
Sekar, G. Chem. Commun. 2011, 47, 5076−5078. (j) Huang, M.;
Wang, L.; Zhu, X.; Mao, Z.; Kuang, D.; Wan, Y. Eur. J. Org. Chem.
2012, 4897−4901. (k) Liao, B.-S.; Liu, S.-T. J. Org. Chem. 2012, 77,
6653−6656.
(16) For the generation of aryl radical species by a single electron
transfer to aryl halides, see: (a) Rossi, R. A.; Pierini, A. B.; Penenory, A.
́
̃
̃
B. Chem. Rev. 2003, 103, 71−167. (b) Shirakawa, E.; Itoh, K.;
Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537−15539.
(c) Shirakawa, E.; Hayashi, Y.; Itoh, K.; Watabe, R.; Uchiyama, N.;
Konagaya, W.; Masui, S.; Hayashi, T. Angew. Chem. 2012, 124, 222−
225; Angew. Chem., Int. Ed. 2012, 51, 218−221.
(17) For the generation of copper nitrene species from copper
reagents and azides and their application for the organic synthesis, see:
(a) Gephart, R. T, III; Warren, T. H. Organometallics 2012, 31, 7728−
7752. (b) Badiel, Y. M.; Krishnaswamy, A.; Melzer, M. M.; Warren, T.
H. J. Am. Chem. Soc. 2006, 128, 15056−15057. (c) Badiei, Y. M.;
Dinescu, A.; Dai, X.; Palomino, R. M.; Heinenmann, F. W.; Cundari,
T. R.; Warren, T. H. Angew. Chem. 2008, 120, 10109−10112; Angew.
Chem., Int. Ed. 2008, 47, 9961−9964. (d) Wiese, S.; Badiei, Y. M.;
Gephart, R. T.; Mossin, S.; Varonka, M. S.; Melzer, M. M.; Meyer, K.;
Cundari, T. R.; Warren, T. H. Angew. Chem. 2010, 122, 9034−9039;
Angew. Chem., Int. Ed. 2010, 49, 8850−8855. (e) Gephart, R. T., III;
Huang, D. L.; Aguila, M. J. B.; Schmidt, G.; Shahu, A.; Warren, T. H.
Angew. Chem. 2012, 124, 6594−6598; Angew. Chem., Int. Ed. 2012, 51,
6488−6492. (f) Aguila, M. J. B.; Badiei, Y. M.; Warren, T. H. J. Am.
Chem. Soc. 2013, 135, 9399−9408. (g) Han, H.; Park, S. B.; Kim, S. K.;
Chang, S. J. Org. Chem. 2008, 73, 2862−2870.
(18) Qu and co-workers demonstrated that copper−nitrogen bonds
of diamine-ligated copper (I) nitrene complexes, [(N···N)Cu−N−R],
show single-bonded character in some cases, e.g., when the substituent
R is methyl group, from density functional theory analysis. Meng, Q.;
Wang, F.; Qu, X.; Zhou, J.; Li, M. THEOCHEM 2007, 815, 111−118
For more studies on the structure of copper nitrene species, see ref 17a
and references cited therein.
(4) Monguchi, Y.; Maejima, T.; Mori, S.; Maegawa, T.; Sajiki, H.
Chem.Eur. J. 2010, 16, 7372−7375.
(5) Maejima, T.; Shimoda, Y.; Nozaki, K.; Mori, S.; Sawama, Y.;
Monguchi, Y.; Sajiki, H. Tetrahedron 2012, 68, 1712−1722.
(6) Aromatic azides were recently synthesized by copper-catalyzed
cross-coupling reactions between aryl halides and NaN3; see: (a) Zhu,
W.; Ma, D. Chem. Commun. 2004, 888−889. (b) Andersen, J.;
Madsen, U.; Bjorkling, F.; Liang, X. Synlett 2005, 2209−2213.
̈
(7) Cho, Y. A.; Kim, D.-S.; Ahn, H. R.; Canturk, B.; Molander, G. A.;
Ham, J. Org. Lett. 2009, 11, 4330−4333.
(8) For the pioneering observation of a copper-mediated in situ
direct formation of anilines from aryl bromides and sodium azide; see
(a) Qin, Z.; Kastrati, I.; Chandrasena, R. E. P.; Liu, H.; Yao, P.;
Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R. J. J. Med. Chem. 2007,
50, 2682−2692. (b) Cosner, C. C.; Markiewicz, J. T.; Bourbon, P.;
Mariani, C. J.; Wiest, O.; Ruoji, M.; Rosenbsum, A. I.; Huang, A. Y.;
Maxfield, F. R.; Helquist, P. J. Med. Chem. 2009, 52, 6494−6498.
(9) (a) Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010, 75, 3311−
3316. (b) Markiewicz, J. T.; Wiest, O.; Helquist, P. J. Org. Chem. 2010,
75, 4887−4890. (c) Messaoudi, S.; Brion, J.-D.; Alami, M. Adv. Synth.
Catal. 2010, 352, 1677−1687. (d) Goriya, Y.; Ramana, C. V.
Tetrahedron 2010, 66, 7642−7650. (e) Thakur, K. G.; Srinivas, K.
S.; Chiranjeevi, K.; Sekar, G. Green Chem. 2011, 13, 2326−2329.
(10) For a review concerning the copper-catalyzed amination of
haloarenes with azide as the amino source, see: Messaoudi, S.; Brion,
J.-D.; Alami, M. Mini Rev. Org. Chem. 2011, 8, 448−454.
(19) The recovery of Cu(0) species would explain the fact that the
amount of copper could be reduced to 0.5 equiv for the amination of
ethyl 4-bromobenzoate (1) without a significant loss of the reaction
efficiency (94%) as mentioned in our previous paper; see ref 5.
(20) Monguchi, Y.; Nozaki, K.; Maejima, T.; Shimoda, Y.; Sawama,
Y.; Kitamura, Y.; Kitade, Y.; Sajiki, H. Green. Chem. 2013, 15, 490−
495.
(21) Rohrig, U. F.; Majjigapu, S. R.; Grosdidier, A.; Bron, S.;
̈
Stroobant, V.; Pilotte, L.; Colau, D.; Vogel, P.; den Eynde, B. J. V.;
Zoete, V.; Michielin, O. J. Med. Chem. 2012, 55, 5270−5290.
(11) Tetrabutylammonium azide (TBAN3) was not quantitatively
formed, since the IR absorption of TBAN3 in DMA appeared at 1999
cm−1; see the Supporting Information.
(12) If the azide species was copper(II) azide [Cu(N3)2], several
strong absorptions woud be observed between 2050−2150 cm−1 in the
IR spectrum. On the other hand, only a single strong peak should be
observed at 2024 cm−1 together with a shoulder peak at 2070 cm−1, if
copper(I) azide (CuN3) formed; see: Dehnicke, K. Z. Anorg. Allg.
Chem. 1974, 409, 311−319.
(13) The formation of copper azides, such as CuN3 and Cu(N3)2, on
the surface of copper metal by its reaction with HN3 was reported.
Lamnevik, S. In Symposium on Chemical Problems Connected with the
Stability of Explosions; Hansson, J., Ed.; Forsvarets Forskingsanst.:
Stockholm, 1969; pp 21−33.
(14) (a) Huisgen, R.; Szeimies, G.; Moebius, L. Chem. Ber. 1967, 100,
2494−2507. (b) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padowa, A., Ed.; Wiley: New York, 1984; pp 1−176. (c) Kolb, H. C.;
Finn, M. G.; Sharpless, K. B. Angew. Chem. 2001, 113, 2056−2075;
F
dx.doi.org/10.1021/jo401474k | J. Org. Chem. XXXX, XXX, XXX−XXX